Trenched sample assembly for detection of analytes with electromagnetic read-write heads

ABSTRACT

Described are embodiments of an invention for a sample assembly with trenches for detection of analytes with electromagnetic read heads. The sample assembly includes an outer layer with at least one sample trench. The sample trench includes a first set of antibodies that are bonded on a first surface of a base layer. Target antigens are bonded with the first set of antibodies, and a second set of antibodies are bonded to the target antigens. Further, the sample trench includes nanoparticles that are bonded to the second set of antibodies. A head module includes a write head for magnetizing nanoparticles and a read sensor for detecting the magnetized nanoparticles, and thus, the target antigens. The sample trench constrains the biological sample, and thus the target antigen, during the preparation and subsequent analysis of the biological sample. Accordingly, the target antigen is aligned with read elements of a head module such that the target antigen is reliably and accurately detected. Further, to ensure reliable and accurate detection, the outer layer is formed with a low friction material allowing the read head to remain in contact with the upper surface of the outer layer during the process of detection.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is related to cofiled, copending and coassignedU.S. patent application Ser. No. 12/888,388 entitled “DETECTION OFANALYTES VIA NANOPARTICLE-LABELED SUBSTANCES WITH ELECTROMAGNETICREAD-WRITE HEADS”, Ser. No. 12/888,394 entitled “READ-AFTER-WRITEDETECTION OF ANALYTES VIA NANOPARTICLE-LABELED SUBSTANCES”, U.S. patentapplication Ser. No. 12/888,403 entitled “A SERVO CONTROL CIRCUIT FORDETECTING ANALYTES VIA NANOPARTICLE-LABELED SUBSTANCES WITHELECTROMAGNETIC READ-WRITE HEADS”, and U.S. patent application Ser. No.12/888,408 entitled “A CIRCUIT FOR DETECTING ANALYTES VIANANOPARTICLE-LABELED SUBSTANCES WITH ELECTROMAGNETIC READ-WRITE HEADS,”all of which were filed on Sep. 22, 2010 and are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to analytical devices and processes, andmore particularly, to devices and processes that incorporateelectromagnetic write-heads and magneto-resistive read-sensors to detecttarget antigens.

BACKGROUND OF THE INVENTION

It is known that antibodies bind with antigens as part of the humandisease defense system. Presently, antigens are detected by suchtechniques as immunofluorescence, immunoperoxidase, or enzyme-linkedimmunosorbent assay (ELISA), each of which then employs a microscope forvisual detection of the target antigen. It is desirable to exploit theuse of magnetic signaling technology to automate the detection ofanalytes, such as antigens, and to further apply this technology to thedetection of any biological matter.

SUMMARY OF THE INVENTION

Described are embodiments of an invention for a sample assembly withtrenches for detection of analytes with electromagnetic read heads. Thesample assembly includes an outer layer with at least one sample trench.The sample trench includes a first set of antibodies that are bonded ona first surface of a base layer. Target antigens are bonded with thefirst set of antibodies, and a second set of antibodies are bonded tothe target antigens. Further, the sample trench includes nanoparticlesthat are bonded to the second set of antibodies. A head module includesa write head for magnetizing nanoparticles and a read sensor fordetecting the magnetized nanoparticles, and thus, the target antigens.The sample trench constrains the biological sample, and thus the targetantigen, during the preparation and subsequent analysis of thebiological sample. Accordingly, the target antigen is aligned with readelements of a head module such that the target antigen is reliably andaccurately detected. Further, to ensure reliable and accurate detection,the outer layer is formed with a low friction material allowing the readhead to remain in contact with the upper surface of the outer layerduring the process of detection.

For example, a method of forming a sample assembly of a biologicalsample having target antigens includes forming at least one sampletrench within an outer layer, such that the sample trench has a bottomsurface. Further, a base layer is formed and a first set of antibodiesare bonded on a first surface of the base layer within the sampletrench. The sample trench having the first set of bonded antibodies isexposed to a biological sample having target antigens. The targetantigens bond with the first set of antibodies within the sample trench.A second set of antibodies are bonded to nanoparticles. In oneembodiment the first and second set of antibodies are biologicallyidentical. Further, the target antigens within the sample trench areexposed to the second set of antibodies that are bonded with thenanoparticles. The second set of antibodies bond with the targetantigens within the sample trench.

In one embodiment, the method includes forming a plurality of magneticservo alignment marks on the sample assembly. The method of forming theplurality of magnetic servo alignment marks includes forming at leastone servo alignment trench in the outer layer parallel to the sampletrench. Further, the step of forming the plurality of magnetic servoalignment marks includes filling the servo alignment trench with tapeink, curing the tape ink and forming the plurality of magnetic servoalignment marks in the cured tape ink.

In one embodiment, the method includes magnetizing the nanoparticles.Further, the nanoparticles are magnetized by a write head. In oneembodiment, the base layer is formed on the bottom surface of the sampletrench. In another embodiment, the outer layer is formed on the baselayer and the base layer is exposed by the bottom surface of the sampletrench.

In one embodiment the outer layer is selected from the group consistingof diamond-like-carbon, polytetrafluoroethylene, aluminum oxide, andpolyamides. The first set of antibodies are bonded to the target antigenwith a bonding material selected from the group consisting of amide,self-assembled-monolayers (SAMS), alkoxysilane, organic functionaltrialkoxysilane, and thiol containing surface modifiers.

In an embodiment of detecting target antigens in a biological sample ona sample assembly, the method includes forming at least one sampletrench within an outer layer, such that the sample trench has a bottomsurface. Further, a base layer is formed and a first set of antibodiesare bonded on a first surface of the base layer within the sampletrench. The sample trench having the first set of bonded antibodies isexposed to a biological sample having target antigens. The targetantigens bond with the first set of antibodies within the sample trench.A second set of antibodies are bonded to nanoparticles. In oneembodiment, the first and second set of antibodies are biologicallyidentical. Further, the target antigens within the sample trench areexposed to the second set of antibodies that are bonded with thenanoparticles. The second set of antibodies bond with the targetantigens within the sample trench. A head module is swept over thesample assembly. The head module includes at least one magneto-resistiveread sensor to detect the target antigens.

In an embodiment of a sample assembly including a biological samplehaving a target antigen, the sample assembly includes an outer layerhaving at least one sample trench. The sample trench has a bottomsurface. The sample assembly also includes a base layer. The sampletrench includes a first set of antibodies bonded on a first surface ofthe base layer. The sample trench further includes target antigens whichare bonded with the first set of antibodies. Further the sample trenchincludes a second set of antibodies which are bonded to the targetantigens and nanoparticles bonded to the second set of antibodies. Thefirst and second set of antibodies are biologically identical.

For a fuller understanding of the present invention, reference should bemade to the following detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top view of a sample assembly, not drawn to scale, inaccordance with an embodiment of the invention;

FIG. 2A is a cross-sectional view of a portion of a sample assembly, notdrawn to scale, including a sample trench in accordance with anembodiment of the invention;

FIG. 2B is a cross-sectional view of a portion of a sample assembly, notdrawn to scale, including a sample trench in accordance with anotherembodiment of the invention;

FIG. 2C is a cross-sectional view of sample assembly, not drawn toscale, including sample trenches and an alignment trench in accordancewith an embodiment of the invention;

FIG. 3 is a cross-sectional view of a portion of a sample assembly, notdrawn to scale, including a biological sample in accordance with anembodiment of the invention;

FIG. 4 is a flow chart illustrating steps of an analytic process inaccordance with an embodiment of the invention;

FIG. 5 is a flow chart illustrating additional steps of an analyticprocess in accordance with an embodiment of the invention;

FIG. 6 illustrates control circuitry for the X-axis and Y-axis motion ofthe head module in an embodiment of the invention; and

FIG. 7 illustrates read and write circuitry in an embodiment of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in exemplary embodiments in thefollowing description with reference to the Figures, in which likenumbers represent the same or similar elements. While the invention isdescribed in terms of the best mode for achieving the invention'sobjectives, it will be appreciated by those skilled in the art thatvariations may be accomplished in view of these teachings withoutdeviating from the spirit or scope of the invention.

Described are embodiments of an invention for a sample assembly withtrenches for detection of analytes with electromagnetic read heads. Thesample assembly includes an outer layer with at least one sample trench.The sample trench includes a first set of antibodies that are bonded ona first surface of a base layer. Target antigens are bonded with thefirst set of antibodies, and a second set of antibodies are bonded tothe target antigens. Further, the sample trench includes nanoparticlesthat are bonded to the second set of antibodies. A head module includesa write head for magnetizing nanoparticles and a read sensor fordetecting the magnetized nanoparticles, and thus, the target antigens.The sample trench constrains the biological sample, and thus the targetantigen, during the preparation and subsequent analysis of thebiological sample. Accordingly, the target antigen is aligned with readelements of a head module such that the target antigen is reliably andaccurately detected. Further, to ensure reliable and accurate detection,the outer layer is formed with a low friction material allowing the readhead to remain in contact with the upper surface of the outer layerduring the process of detection.

FIG. 1 is a top view of a sample assembly 100, not drawn to scale, inaccordance an embodiment of the invention. The sample assembly 100includes a substrate 199. The substrate 199 may comprise, withoutlimitations, a Peltier hard-substrate, a glass substrate, a polyethyleneterephthalate (PET, which is commonly known by the trade name of Mylar™)substrate, a flexible-substrate, or other materials having similarproperties. The term “substrate” refers to any supporting structure,including, but not limited to, the substrates described above. Further,the substrate may include of more than one layer of material.

An outer layer 253 is formed over substrate 199. Deposition techniquesutilized herein include, but are not limited to, photolithography,silk-screening, and other similar processes. The outer layer maycomprise diamond-like-carbon (DLC), polytetrafluoroethylene, aluminumoxide, polyamides, or other low-friction materials known in the art. Theouter layer 253 may be formed to a thickness of between 0.2 to 60microns. The outer layer 253 includes sample trenches 180. The processof forming the sample trenches 180 is described with respect to FIGS. 2Aand 2B.

One embodiment of forming sample trenches 180 is illustrated in FIG. 2A.In this embodiment, a base layer 252 is formed on substrate 199. Baselayer 252 may comprise nonmagnetic materials such as gold, silicon, orSiO₂, or other materials having similar magnetic properties, withoutlimitation. An outer layer 253 is then formed on base layer 252. Outerlayer 253 has an upper surface 254. A plurality of sample trenches 180are formed within outer layer 253. Sample trenches 180 may be formed byknown methods in the art including laser milling, x-ray milling, orphotolithographically. Sample trenches 180 may be formed to have a depthof between 0.2 to 60 microns. It should be understood by one of ordinaryskill in the art that, while only one sample trench is shown, aplurality of sample trenches 180 may be formed within the outer layer253 with the same method described herein. Each sample trench 180 isformed having a bottom surface 255. In one embodiment, the bottomsurface of the trench exposes base layer 252.

Another embodiment of forming sample trenches 180 is described withrespect to FIG. 2B. In this embodiment, outer layer 253 is formed onsubstrate 199. The outer layer 253 has an upper surface 254. A pluralityof sample trenches 180 are formed within outer layer 253. Sampletrenches 180 may be formed by known methods in the art including lasermilling, x-ray milling, or photolithographically. Sample trenches may beformed to have a depth of between 0.2 to 60 microns. It should beunderstood by one of ordinary skill in the art that, while only onesample trench is shown, a plurality of sample trenches 180 may be formedwithin the outer layer 253 with the same methods described herein. Eachsample trench 180 is formed having a bottom surface 255. Base layer 252is formed within each sample trench 180 and on the bottom surface 255 ofeach sample trench 180. Base layer 252 may comprise nonmagneticmaterials such as gold, silicon, or SiO₂, or other materials havingsimilar magnetic properties, without limitations. As shown in FIG. 2B,the base layer 252 only partially fills sample trenches 180. There aremany embodiments in which base layer 252 may be formed to only partiallyfill sample trenches 180. For example, in one embodiment, base layer 252may be formed conformally over the outer layer 253 and within sampletrenches 180. Base layer may then be removed by etching or planarizationtechniques known in the art. Alternatively, the base layer 252 may beselectively deposited by known methods in the art. The describedembodiment of forming a base layer 252 only within the sample trench 180is particularly advantageous in embodiments in which expensive materialsare utilized, such as gold since much less material is required to formthe base layer 252.

As shown in FIG. 1, eight sample trenches 180 may be formed tocorrespond to the head module 104 of the IBM® TS1130 writing with eightwrite elements 106 and reading with eight read sensors 108simultaneously, as further explained below. The sample trenches 180 areparallel to each other and extend along the Y-axis.

In one embodiment, as shown in FIGS. 1 and 2C, the outer layer 253further includes at least one servo alignment track 194 with a pluralityof magnetic servo alignment marks 193. The servo alignment track 194 isparallel with the sample trenches 180 and extends along the Y-axis. Theservo alignment track 194 may be a servo alignment trench 194 with aplurality of magnetic servo alignment marks 193. FIG. 2C shows a crosssection of substrate 199 along the X-axis illustrating an embodiment inwhich an alignment trench 194 is formed within outer layer 253. Forsimplicity of illustration, base layer 252 is not illustrated in FIG.2C. Alignment trench 194 may be formed in the same manner as describedfor forming sample trenches 180 shown in FIGS. 2A and 2B. In oneembodiment, alignment trench 194 is formed simultaneously with theformation of sample trenches 180. Specifically, alignment trench 194 maybe formed by known methods in the art including laser milling, x-raymilling, or photolithographically. Alignment trench 194 may have a depthof between 0.2 to 60 microns. It should be understood by one of ordinaryskill in the art that, while only one alignment trench 194 is shown, aplurality of alignment trenches 194 may be formed within the outer layer253 as described herein. For example, alignment trenches 194 could beformed between each of the sample trenches 180.

In this embodiment, sample trenches 180 are masked and the servoalignment trench 194 is filled with tape ink. The tape ink, whichcontains magnetic recording particles in a polymer matrix, is cured bymethods known in the art. Magnetic encoded servo alignment marks 193 aresubsequently encoded in the cured tape ink.

In another embodiment, magnetic encoded servo alignment marks 193 areencoded on a piece of magnetic tape which is adhered to outer layer 253.Further, the magnetic encoded servo alignment marks 193 may be encodedby the manufacturer of substrate 199 on the magnetic tape. Magneticencoded servo alignment marks 193 may be in the form of timing basedservo marks as taught by U.S. Pat. No. 7,639,448 and entitled“Differential Timing Based Servo Pattern for Magnetic-Based StorageMedia,” which is hereby incorporated by reference in its entirety. Servoalignment marks 193 are read by read sensor 106 and used to keep thewrite elements 108 and read sensors 106 in alignment with sampletrenches 180 along the X-axis while the head module 104 moves relativeto sample trenches 180 along the Y-axis.

Still further, in one embodiment the alignment marks 193 may benon-magnetic marks. For example, the alignment marks may belithographed, silk-screened or ink-jet printed, and read with an opticallaser.

The sample trenches 180 include a biological sample having a targetantigen. Sample trenches 180 act to constrain the biological sample, andthus the target antigen 210, during the preparation and subsequentanalysis of the biological sample, as discussed below. For example, thesample trenches 180 prevent the biological sample from being rinsed awayduring a rinse step. Further, the sample trenches 180 allow thebiological sample and the target antigen to be constrained to an areathat is aligned with read elements 108, such that detection of targetantigen 210 is reliably and accurately detected.

The preparation of the biological sample with target antigens 210 withinthe sample trench 180 is discussed further with respect to FIGS. 3 and4. FIG. 3 illustrates preparation of biological sample including thetarget antigen 210 on sample assembly 100. FIG. 4 illustrates the stepsof preparing sample assembly 100 and detecting the target antigens 210.For simplicity of explanation, FIG. 3 shows the embodiment in which thebase layer 252 is formed within the sample trench 180 and a singlesample trench 180. However, it should be understood that the base layermay be formed by any of the methods described herein and a plurality ofsample trenches 180 may be formed. As discussed above, an outer layer253 is formed on substrate 199. In step 402, at least one sample trench180 is formed in outer layer 253. Base layer 252 is formed on the bottomsurface 255 of the sample trench 180.

In step 404, antibodies 208A are bonded within sample trenches 180 tothe first surface of base layer 252. The antibodies 208A may be bondedwithin the sample trenches to the base layer 252 via bonds 206A such asamide, self-assembled-monolayers (SAMS), alkoxysilane, organicfunctional trialkoxysilane, thiol bonds, or the like. It is important tonote that the material of base layer 252 facilitates the bonding ofantibody 208A within sample trench 180.

In one embodiment, it is preferred that bond 206A is applied only to thefirst surface of base layer 252. In one example, the bonding comprisesfirst coating base layer 252 with amide, self-assembled-monolayers(SAMS), alkoxysilane, or thiol and then placing a solution of antibodies208A on substrate 199 and gently rocking substrate 199 for a period oftime, up to six hours. Amide refers to organic compounds that includethe functional group including an acyl group, with the chemical notationC═O, linked to a nitrogen (N) atom. A SAM is an organized layer ofamphiphilic molecules in which one end of the molecule, the “headgroup,” shows a special affinity for gold, silicon, or SiO₂, such asthat utilized in base layer 252. At the terminal end, the opposite endof the SAM from the “head group” is a functional group. In oneembodiment, the first set of antibodies 208A are attached to thisfunctional group in step 404. Lastly, a thiol is a compound thatincludes the functional group composed of a sulfur atom and a hydrogenatom (—SH). Being the sulfur analog of an alcohol group (—OH), thisfunctional group is referred to either as a thiol group or a mercaptangroup.

There are generally five known isotopes (types) of antibodies 208A and208B for mammals. In FIG. 3, the Y-shape of antibodies 208A and 208B arethat of monomer antibodies. There are three isotopes of monomerantibodies: IgD, IgE, and IgG, where the prefix Ig is the symbol forImmunoglobulin, and these monomer antibodies each have one unit of Ig.There is only one isotope of a dimer antibody, IgA, which has two Igunits. Finally, there is only one isotope of pentamer antibody, IgM,which has five Ig units. These antibodies are further described incopending and coassigned U.S. patent application Ser. No. 12/888,388entitled “DETECTION OF ANALYTES VIA NANOPARTICLE-LABELED SUBSTANCES WITHELECTROMAGNETIC READ-WRITE HEADS”, which is incorporated herein byreference. The analytical process described herein may be used in humanmedicine, veterinarian medicine, and, as well as to other biologicalanalyses.

In one embodiment, step 404 may include a step of rinsing substrate 199with water or another rinsing agent to remove any antibodies 208A thatare not bonded within sample trenches 180. In all rinsing stepsdiscussed herein a surfactant may be added to the water or rinsing agentto reduce surface tension. In one example, the surfactant may include adetergent solution.

In step 406, antibodies 208A bonded within sample trench 180 are exposedto a biological sample including target antigens 210. In one example,this is accomplished by placing a blood sample or other biologicalsample on substrate 199. As shown in FIG. 3, the target antigens 210bond to monomer antibodies 208A at antigen receptors 209A. The antigenreceptors 209A are diagrammatically shown to be at the v-shaped end ofantibodies 208A. As shown, each monomer antibody 208A has two antigenreceptors 209A. Step 406 may include the repetitive rocking of substrate199 to facilitate bonding of the target antigens 210 with antibodies208A at antigen receptors 209A. For example the substrate is gentlyrocked for up to six hours. Further, step 406 may include a step ofrinsing substrate 199 with water or another rinsing agent to removeantigens 210 not bonded to antibodies 208A

Target antigens 210 may comprise cancer cells, viruses, or bacteria. Inone embodiment, the target antigens 210 are viruses such as HumanPapilloma Virus (HPV) which is known to lead to cancer. It is importantto note that the antibodies 208A utilized in step 404 are specificallychosen based on the targeted antigens 210 utilized in step 406.

In step 408, a second set of antibodies 208B are bonded withnanoparticles 212. It is important to note that the first set ofantibodies 208A and the second set of antibodies 208B are biologicallyidentical, as both bond to the same target antigen 210. In oneembodiment, the second set of antibodies 208B are bonded withnanoparticles 212 in parallel with steps 404 and 406. In otherembodiments, the second set of antibodies 208B may be bonded withnanoparticles 212 before or after steps 404 and 406. The nanoparticles212 include a magnetic inner core 216 and a outer shell 214. Magneticinner cores 216 may comprise hard magnetic materials with highcoercivity, such as Fe₂O₃, CrO₂, and Barium Ferrite BaFe. For example,magnetic inner cores 216 may comprise iron oxide based nanoparticlematerials, including M Fe₂O₄ (where M may be Co, Ni, Cu, Zn, Cr, Ti, Ba,or Mg) nanomaterials, and iron oxide coated nanoparticle materials orother structures with similar functionality.

In one embodiment, step 408 further includes preparing the nanoparticles212 prior to bonding the nanoparticles 212 to antibodies 208A. Thepreparation of nanoparticles 212 is described in FIG. 5. Magnetizednanoparticles are prone to agglomerate and form lumps. Therefore, instep 502 the magnetic inner cores 216 of nanoparticles 212 aredemagnetized. In one embodiment, the magnetic inner cores 216 ofnanoparticles 212 are heated above their Curie temperature todemagnetize the inner cores 216. The heated magnetic inner cores 216 areallowed to cool. The step of demagnetization keeps the inner cores 216of nanoparticles 212 as individual particles.

In another embodiment, the step of demagnetizing the inner cores 216 ofnanoparticles may be omitted. The process of manufacturing the innercores 216 of nanoparticles may include a step of high temperaturesintering. Thus, the manufacturing process of the nanoparticles 212 maydemagnetize the inner cores 216. The formation of nanoparticles istaught without limitation by U.S. Pat. No. 6,962,685, entitled“Synthesis of Magnetite Nanoparticles and the Process of Forming,” whichis hereby incorporated by reference in its entirety.

Returning to FIG. 5, in step 504 the inner cores 216 are coated with anouter-shell 214 of nonmagnetic gold, silicon, or SiO₂, to createnanoparticles 212. Antibodies 208B are bonded to nanoparticles 212 viabonds 206B, such as amide, self-assembled-monolayers (SAMS),alkoxysilane, organic functional trialkoxysilane, or thiol bonds. Thisbonding may be accomplished by first coating nanoparticles 212 withamide, self-assembled-monolayers (SAMS), alkoxysilane, organicfunctional trialkoxysilane, or thiol. It is important to note that thematerial used for the outer shell 214 facilitates the bonding ofantibody 208A within sample trench 180. The nanoparticles 212 may beplaced in a solution including the second set of antibodies 208B andgently rocking this solution for a period of time. The repetitiverocking of substrate 199 facilitates bonding of the second set ofantibodies 208B with the nanoparticles 212. For example, the substrateis gently rocked for up to six hours. Further, step 408 may include astep of rinsing substrate 199 with water or another rinsing agent toremove nanoparticles 212 not bonded to antibodies 208B.

In step 410, target antigens 210 are exposed to the second set ofantibodies 208B bonded to nanoparticles 212. This may be done by placinga solution of nanoparticle-labeled antibodies 208B on substrate 199. Asshown in FIG. 3, the target antigens 210 bond with the antigen receptors209B of antibodies 208B. Step 410 may include the repetitive rocking ofsubstrate 199 to facilitate bonding of the target antigens 210 withantibodies 208B at antigen receptors 209B. For example, the substrate isgently rocked for up to six hours. Further, step 410 may include a stepof rinsing substrate 199 with water or another rinsing agent to removenanoparticles 212 not bonded to target antigens 210.

In the embodiment in which substrate 199 is a Peltier substrate, theprocess may include an optional step of applying a DC voltage of a firstpolarity to the Peltier substrate. Applying a DC voltage of a firstpolarity heats the surface of the substrate 199 and dries the biologicalsample within the sample trench 180. A DC voltage of a second andopposite polarity may be applied to Peltier substrate, to cool thesurface of the substrate. In an alternate embodiment, the Peltiersubstrate freezes the biological sample.

Returning to FIG. 1, head module 104 includes electromagneticwrite-heads 106 and magneto-resistive read-sensors 108 arranged inpairs, such that each write head 106 is paired with a read sensor 108.The write head 106 may be a thin film write element. The electromagneticwrite-heads 106 first write to sample trenches 180, and then theadjacent magneto-resistive read-sensors 106 immediately reads fromsample trenches 180, which is referred to as a read-after-writeoperation. In an exemplary embodiment of the invention, the sampleassembly 100 has eight sample trenches 180 corresponding to eight bitsin a byte. Accordingly, in this embodiment the head module includeseight electromagnetic write-head 106 and magnetoresistive read-sensor108 pairs. Advantageously, this is the same number of write heads andread sensors in a typical head module used in magnetic tape driveproducts, such as IBM® TS1130.Therefore, in one embodiment the headmodule 104 may be an IBM® TS1130 head module. It should be understood,however, any number of sample trenches 180 may be used, and the numberof electromagnetic write-head 106 and magneto-resistive read-sensor 108pairs in head module 104 may be any number. The number may be in therange from one to the number of electromagnetic write-head andmagneto-resistive read-sensor pairs the head module 104. For example, inan embodiment in which there are sixteen such electromagnetic write-headand magneto-resistive read-sensor pairs, such as in a head module of anIBM® 3480 tape drive, the number of sample trenches may be sixteen. Inone embodiment, the number of sample trenches 180 is an integralmultiple of the number of write-head 106 and read-sensor 108 pairs.Still further, in one embodiment, the write-head 106 and the read-sensorare not separate devices. Instead a single head may perform thefunctions of both the write-head 106 and read-sensor 108.

As mentioned above, the sample trenches 180 may have spacing from onesample trench to the adjacent sample trench along the X-axis to matchthe spacing from one read sensor 108 to the adjacent read sensor 108along the X-axis. In one embodiment the spacing between one sampletrench 180 and an adjacent sample trench 180 is 166.5 microns to matchthe read sensor to read sensor spacing of the IBM® TS1130 tape drive.

Write-heads 106 may be any write head known in the art. In oneembodiment write-heads 106 comprise miniature electromagnets, with acoil sandwiched between two poles. Read-sensors 108 may be anisotropicmagneto-resistive (AMR), giant magneto-resistive (GMR), or tunnelmagneto-resistive (TMR) read-sensors, or other devices with similarfunctionality known in the art. GMR read-sensors, which are also knownas spin-valve read-sensors, typically have an internal anti-parallelpinned layer for increased sensitivity. TMR read-sensors may utilize atunnel barrier layer to augment the GMR internal structure and toprovide increased sensitivity.

As shown in FIG. 1, write-head 106 may be longer along the X-axisdirection than read-sensor 108. Accordingly, the active sensing portionof read-sensor 108 is smaller than write-head 106 along the X-axis.Write-head 106 is used to magnetize nanoparticle 212 for detection byread-sensor 108 as discussed below. It is advantageous for write-head tobe longer in the X-direction than read-sensor 108 because it preventsread-sensor from encountering unmagnetized nanoparticles 212, and thus,registering a false-negative detection of target antigen 210.

Head module 104 is kept in linear alignment with sample trenches 180along the X-axis by position-error-servo (PES) read-head 192, whichreads magnetically encoded servo-alignment marks 193 from servo track194 on sample assembly 100. PES read-head 192 may be, for example, anAMR, GMR, or TMR read-sensor. In the example illustrated in FIG. 1,servo-alignment marks 193 shown are Timing Based Servo (TBS)servo-alignment marks such as those used in IBM® Linear Tape Open (LTO)tape drive products (e.g., IBM® tape product models TS1120 and TS1130).U.S. Pat. No. 6,320,719, entitled “Timing Based Servo System forMagnetic Tape Systems,” is hereby incorporated by reference in itsentirety for its showing of Timing Based Servo control and TBSservo-alignment marks. U.S. Pat. No. 6,282,051, entitled “Timing BasedServo System for Magnetic Tape Systems,” is hereby incorporated byreference in its entirety for showing the writing of TBS servo-alignmentmarks.

In step 412 of FIG. 4, the process of detecting the target antigens 210includes sweeping head module 104 with at least one magneto-resistiveread sensor 108 over the sample assembly 100. In one embodiment headmodule 104 is moved linearly from left to right along the +Y axisrelative to a stationary sample assembly. In another embodiment, thesample assembly 100 is swept linearly from right to left along the −Yaxis past a stationary head module 104. If substrate 199 is of aflexible polyethylene terephthalate material, then in one embodiment,this right-to-left motion may be performed as data read-write operationsin a magnetic tape drive. The head module 104 may sample a single sampletrench 180, or simultaneously sample a plurality of sample trenches 180.As an alternate embodiment, head module 104 comprises a helical-scanrotary head module, and the Y-axis of the sample trench 180 is at anangle to the substrate 199. In this embodiment the sample trenches 180are much shorter in length such that alignment of the head module 104with sample trenches 180 may be accomplished without alignment marks193. In one embodiment the IBM® MSS 3850 helical-scan tape drive may beutilized to detect analytes.

In one embodiment, the head module 104 comes into physical contact withthe upper surface 254 of the outer layer 253 during the sweeping step of412. Keeping the head module 104 in physical contact with the uppersurface ensures that the head module 104 is kept at a known Z-axisposition and assists with alignment of head module 104 with sampletrenches 180. As discussed above, the outer layer 253 may comprisediamond-like-carbon, polytetrafluoroethylene, aluminum oxide,polyamides, or other low-friction materials known in the art.Accordingly, the low friction material of the outer layer assists thehead module 104 to smoothly sweep the sample trenches 180 while inphysical contact with the upper surface 254 of outer layer 253, suchthat the target antigens of the biological sample is reliably andaccurately detected.

As discussed with respect to step 502 in FIG. 5, in some embodiments theinner core 216 of nanoparticles are demagnetized. Accordingly, in thisembodiment, as part of step 412, write-head 106 writes to nanoparticles212 to magnetize inner cores 216 of nanoparticles. Write-head 106 writeswith a constant DC magnetic polarity for the duration of the sweepingstep 412, such that there are no unwritten regions of sample assembly100. In one embodiment, write-head 106 writes withmagnetically-overlapping write pulses. Further in step 412, read-sensor108 detects the freshly magnetized inner cores 216 of nanoparticles 212,and thus detects target antigens 210. Read-sensor can detect the targetantigens 210 because nanoparticles 212 are bonded to antibodies 208B,which in turn are bonded to target antigens 210.

Write head 106 magnetizes inner cores 216 of nanoparticles 212 along theY-axis, which is the longitudinal direction of recording in the tapedrive industry. Read-sensor 108 magnetically detects nanoparticles 212along the Y-axis. As a result in step 412, the nanoparticles 212 may bemagnetized by write-head 106 and then immediately and magneticallydetected by read-sensor 108 during a single sweep of the sample trenches180. As discussed above, this process is referred to as aread-after-write operation. In one embodiment, the write-head 106 andread-sensor 108 are separated by a magnetic shield (not shown) toprevent cross-talk between write-head 106 and read-sensor 108 duringstep 412.

Alternatively, the steps of magnetizing nanoparticles 212 and the stepof detecting the nanoparticles 212 may be performed separately. Forexample, write head 106 magnetizes inner cores 216 of nanoparticles 212along the Y-axis of sample assembly 100. In one embodiment, write-head106 is then turned off. Subsequently, read-sensor 108 magneticallydetects nanoparticles 212 along the Y-axis. The read module sensor 108may be swept across sample trenches 180 along the Y-axis in both the +Yand −Y directions. Accordingly, read-sensor 108 can repeatedly check formagnetized nanoparticles 212, thus ensuring that all target antigens 210are detected.

In an embodiment in which the number of sample trenches 180 are greaterthan the number of write-head 106 and read-sensor 108 pairs in headmodule 104, the head module 104 may scan the sample trenches 180 in aserpentine fashion. The head module 104 performs a scan in the +Ydirection, as head module 104 only provides read-after-write capabilityin the +Y direction as shown in FIG. 1. Then, a second head module (notshown) comprising a mirror image of head module 104, conducts aread-after-write operation in the −Y direction.

The coercivity of a magnetic inner core 216 may be chosen selectivelydepending upon the target antigen 210 to be detected. For example,nanoparticles 212 with magnetic inner cores 216 of different coercivityvalues may be respectively bonded to different types of antibodies 208Aand 208B to detect various types of target antigens 210 on the sampleassembly 100 simultaneously. Nanoparticles 212 may have differentmagnetic properties associated with each antigen-antibody combination.Read-sensor 108 detects the different magnetic properties of an innercore 216 based on the materials used for that inner core 216. Asdiscussed above, magnetic inner cores 216 may comprise hard magneticmaterials with high coercivity, such as Fe₂O₃, CrO₂, and Barium FerriteBaFe. For example, magnetic inner cores 216 may comprise iron oxidebased nanoparticle materials, including M Fe₂O₄ (where M may be Co, Ni,Cu, Zn, Cr, Ti, Ba, or Mg) nanomaterials, and iron oxide coatednanoparticle materials or other structures with similar functionality.As a result, in step 412, read-sensor 108 may detect more than one typeof target antigens 210 with a single sweep of the sample assembly 100.

FIG. 6 illustrates an embodiment of a servo control system 600 forcontrolling the motion of head module 104 in the X-axis and Y-axis. Forsimplicity, FIG. 6 illustrates sample assembly 100 including a singletrench 180. In addition, FIG. 6 shows a head module 104 including asingle write-head 106 and read-sensor 108 pair and a PES read head 192.However, it should be understood that the sample assembly 100 mayinclude a plurality of trenches and the head module 104 may include aplurality of write-heads 106 and read sensors 108. PES read-head 192reads servo-alignment marks 193 in servo track 194. Processor 602receives position-error-servo (PES) signals from PES read-head 192.Processor 602 sends a signal to power amplifier 604 to control X-axisactuator 606 based on the PES information. In turn, the X-axis actuator606 controls the motion of head module 104 in the X-axis direction.X-axis actuator 606 is connected to head module 104 via mechanicalconnector 608. Accordingly, head module 104 can be positioned to centerwrite-head 106 and read-sensor 108 on sample trenches 180 of sampleassembly 100. Processor 602 also sends signals to power amplifier 614 tocontrol Y-axis actuator 610 for conducting a scan by head module 104across sample assembly 100. Y-axis actuator 610 is connected to X-axisactuator via mechanical connector 612, such that head module 104 can bemoved along the Y-axis in a controllable manner.

FIG. 7 illustrates one embodiment of a write and read circuitry 700 foruse in writing to the sample trenches 180 (i.e, magnetizingnanoparticles 212) and reading from the sample trenches 180 (i.e,sensing and detecting the magnetized nanoparticles 212). For simplicity,FIG. 7 illustrates sample assembly 100 including a single trench 180. Inaddition, FIG. 7 shows a head module including a single write-head 106and read-sensor 108 pair. However, it should be understood that thesample assembly 100 may include a plurality of trenches and the headmodule 104 may include a plurality of write-heads 106 and read sensors108.

Processor 602 sends signals to power amplifier 704. Power amplifierprovides power to write-head 106 for magnetizing nanoparticles 212.Processor 602 also sends signals to power amplifier 716. Power amplifier716 powers Wheatstone bridge 706. In one embodiment, Wheatstone bridgeincludes read-sensor 108. Thus, read-sensor receives DC current from theWheatstone bridge 706. Read-sensor 108 detects a resistance changeduring step 412 discussed above. The resistance change is based on themagnetic field provided by the magnetized inner cores 216 ofnanoparticles 212. Wheatstone bridge 706 balances out the zero-magnetismresistance of read-sensor 108 such that only the change in resistance ofread-sensor 108 is sent to amplifier 714. The amplifier 714 receives thechange in resistance and sends the change in resistance to processor 602through filter 718. Filter 718 filters out noise. In one embodiment,filter 718 filters out 60 Hz noise which is the type of noise that ispervasive in an office or laboratory setting in which processes of theinvention may be performed.

Processor 602 includes a matched filter 730 and a table 720. Processor602 determines if a nanoparticle 212 was detected, and thus, if a targetantigen 210 has been detected. The change in resistance of read-sensor108 is directly proportional to the magnetic field provided bynanoparticle 212. The change in resistance of read-sensor 108 isdirectly proportional to the magnetic field provided by nanoparticle212.

As discussed above, the coercivity of a magnetic inner core 216 may bechosen selectively depending upon the target antigen 210 to be detected.For example, nanoparticles 212 with magnetic inner cores 216 ofdifferent coercivity values may be respectively bonded to differenttypes of antibodies 208A and 208B to detect various types of targetantigens 210 on the sample assembly 100 simultaneously. Theidentification of the target antigens 210 in the sample trenches 180 maybe facilitated by a lookup table 720 in processor 602. In oneembodiment, the lookup table 720 includes a list of (a) target antigens210, (b) the antibodies 208A and 208B bonded with the target antigens210, and (c) the coercivity of the inner cores 216 of nanoparticles 212bonded to antibodies 208B.

In one embodiment of the invention a correlation calculation isperformed by the write and read circuit of FIG. 7 to improve thedetection accuracy of target antigens. The processor 602 performscorrelation calculation C(y) shown in equation [1] between a detectionsignal profile g(y) read by read-sensor 108 when a nanoparticle 212 isdetected and a matched filter 730.C(y)=∫g(η)h(η−y)dη  Equation [1]In equation [1], η is the integration variable along the Y-axis thatvaries as read-sensor 108 sweeps along the Y-axis. The matched filter730 includes an impulse response h(y) of an ideal signal profile of adetected target nanoparticle 212. Since h(y) is used repetitively, itmay be calculated once and stored as matched filter 730 in processor602.

The range of correlation C(y) is between −1 and +1, where +1 representsan ideal correlation of one hundred percent (100%), and −1 indicates nocorrelation. The electrical waveform g(y) of each potential detection ofa nanoparticle 212 by read-sensor 108 has its correlation C(y)calculated in step 412 of FIG. 4. Processor 602 then compares thiscorrelation C(y) against a threshold correlation value C₀ beforeaccepting the signal g(y) as a valid detection of a nanoparticle 212.This correlation removes spurious electrical noise from actualdetections of nanoparticles, and thus reduces false-positive detectionsof target antigens 210.

In one embodiment, the results of the sweep of step 412 may be displayedto a physician or clinician to inform the physician or clinician of thepresence (or absence) of target antigens 210 in the biological sample.The results may include items such as the target antigen(s) tested for,the types of antibodies used, a simple positive-detection ornegative-detection indication for each antigen, the number ofnanoparticles detected for each antigen to give an indication of theprevalence of the targeted antigen, and the number of rejecteddetections based on the correlation calculation.

The terms “certain embodiments”, “an embodiment”, “embodiment”,“embodiments”, “the embodiment”, “the embodiments”, “one or moreembodiments”, “some embodiments”, and “one embodiment” mean one or more(but not all) embodiments unless expressly specified otherwise. Theterms “including”, “comprising”, “having” and variations thereof mean“including but not limited to”, unless expressly specified otherwise.The enumerated listing of items does not imply that any or all of theitems are mutually exclusive, unless expressly specified otherwise. Theterms “a”, “an” and “the” mean “one or more”, unless expressly specifiedotherwise.

Devices that are in communication with each other need not be incontinuous communication with each other, unless expressly specifiedotherwise. In addition, devices that are in communication with eachother may communicate directly or indirectly through one or moreintermediaries. Additionally, a description of an embodiment withseveral components in communication with each other does not imply thatall such components are required. On the contrary a variety of optionalcomponents are described to illustrate the wide variety of possibleembodiments.

Further, although process steps, method steps, algorithms or the likemay be described in a sequential order, such processes, methods andalgorithms may be configured to work in alternate orders. In otherwords, any sequence or order of steps that may be described does notnecessarily indicate a requirement that the steps be performed in thatorder. The steps of processes described herein may be performed in anyorder practical. Further, some steps may be performed simultaneously, inparallel, or concurrently.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art that,based upon the teachings herein changes and modification may be madewithout departing form this invention and its broader aspects and,therefore, the appended claims are to encompass within their scope allsuch changes and modifications as are within the true spirit and scopeof this invention. Furthermore, it is to be understood that theinvention is solely defined by the appended claims.

What is claimed is:
 1. A method of forming a sample assembly of abiological sample having target antigens, the method comprising: forminga base layer on a substrate; forming an outer layer on the base layer;forming at least one sample trench within the outer layer using one ormore of a milling technique and a lithography technique, wherein saidsample trench has a bottom surface; forming a plurality of magneticservo alignment marks on said sample assembly; bonding a first set ofantibodies within said at least one sample trench on a first surface ofsaid base layer; exposing said at least one sample trench with saidfirst set of bonded antibodies to said biological sample having saidtarget antigens, wherein said target antigens bond with said first setof antibodies within said at least one sample trench; bonding a secondset of antibodies to nanoparticles; and exposing said target antigenswithin said at least one sample trench to said second set of antibodiesbonded to said nanoparticles, wherein said second set of antibodies bondwith said target antigens within said at least one sample trench.
 2. Themethod of claim 1, further comprising applying a voltage to thesubstrate.
 3. The method of claim 2, wherein applying the voltage to thesubstrate reduces a temperature of the substrate.
 4. The method asrecited in claim 2, wherein applying the voltage causes a temperature ofthe substrate to reduce to a value less than a freezing point of atleast one biological sample in the sample trench.
 5. The method asrecited in claim 4, wherein the substrate is a Peltier substrate, andwherein the voltage is a DC voltage.
 6. The method of claim 1, furthercomprising: forming at least one servo alignment trench in said outerlayer, parallel to said sample trench, filling said servo alignmenttrench with tape ink; curing said tape ink; and forming said pluralityof magnetic servo alignment marks in said cured tape ink.
 7. The methodof claim 1, further comprising: magnetizing said nanoparticles using awrite head; aligning the write head with the at least one sample trenchusing a position-error-servo (PES) technique; and detecting saidmagnetized nanoparticles using a read sensor.
 8. The method of claim 1,wherein said outer layer comprises a compound selected from the groupconsisting of diamond-like-carbon, polytetrafluoroethylene, and aluminumoxide wherein said first set of antibodies are bonded to said targetantigen via a bonding material selected from the group consisting ofamide, alkoxysilane, organic functional trialkoxysilane, and thiol. 9.The method of claim 1, wherein the nanoparticles comprise a plurality ofnanoparticles types, each nanoparticle type being characterized by aunique coercivity value, wherein each nanoparticle type is configured tofacilitate detection a different type of target antigen on the sampleassembly simultaneously.
 10. The method of claim 1, wherein the at leastone sample trench comprises a plurality of parallel-oriented sampletrenches, each sample trench being separated from one or more adjacentsample trenches by a distance of approximately 166 microns, and whereinthe at least one sample trench is characterized by a depth in a rangefrom about 0.2 microns to about 60 microns.
 11. The method of claim 1,wherein the bonding the first set of antibodies comprises coating thefirst surface of the base layer with one or compounds selected from agroup consisting of: amides, alkoxysilanes, and thiols; contacting asolution of the first set of antibodies with the first surface of thebase layer; and rocking the first surface of the base layer in contactwith the solution of the first set of antibodies for a predeterminedperiod of time less than or equal to about six hours.
 12. The method asrecited in claim 1, wherein the nanoparticles comprise: a magnetic innercore comprising a material selected from a group consisting of: CrO₂,BaFe, and MFe₂O₄, wherein M is a metal selected from a group consistingof Co, Cr, Ti, Ba and Mg; and a shell comprising a material selectedfrom a group consisting of nonmagnetic gold, silicon and silicondioxide.
 13. The method as recited in claim 1, further comprising:aligning one or more write elements and one or more read sensors of ahead module along an X-axis of the at least one sample trench using atleast some of the servo-alignment marks; coating the first surface ofthe base layer with one or compounds selected from a group consistingof: amides, alkoxysilanes, and thiols; contacting a solution of thefirst set of antibodies with the coated first surface of the base layer;rocking the coated first surface of the base layer in contact with thesolution of the first set of antibodies for a predetermined period oftime less than or equal to about six hours; and magnetizing saidnanoparticles using a write head of the head module; wherein thenanoparticles comprise: a magnetic inner core comprising a materialselected from a group consisting of: CrO₂, BaFe, and MFe₂O₄, where M isa metal selected from a group consisting of Co, Cr, Ti, Ba and Mg; and ashell comprising a material selected from a group consisting of gold,silicon and silicon dioxide; and wherein the tape ink comprises magneticrecording particles disposed in a polymer matrix, wherein the at leastone sample trench comprises a plurality of parallel-oriented sampletrenches, wherein the outer layer comprises a compound selected from thegroup consisting of diamond-like-carbon, polytetrafluoroethylene, andaluminum oxide, and wherein the first set of antibodies are bonded tosaid target antigen via a bonding material selected from the groupconsisting of amide, alkoxysilane, organic functional trialkoxysilane,and thiol.
 14. A method of detecting target antigens in a biologicalsample using a sample assembly having a base layer formed above asubstrate; an outer layer formed above the base layer; at least onesample trench formed in the outer layer using a milling technique; aplurality of first antibodies, at least some of the first antibodieseach being bound to: at least one surface of one or more of the sampletrenches; and one of a plurality of target antigens; a plurality ofsecond antibodies, at least some of the second antibodies each beingbound a target antigen bound to one of the first antibodies; and ananoparticle, the method comprising: aligning a head module with saidsample trench utilizing a plurality of magnetic servo alignment markssweeping said head module over said sample assembly, wherein said headmodule includes at least one magneto-resistive read sensor configured todetect target antigens via the nanoparticles; and detecting at least oneparticular antigen among the plurality of target antigens.
 15. Themethod of claim 14, wherein said step of sweeping said head module oversaid sample assembly includes placing said head module in contact withan upper surface of said outer layer, wherein at least onemagneto-resistive read sensor in said head module detects said targetantigens in said sample trench.
 16. The method of claim 14, furthercomprising utilizing a plurality of magnetic servo alignment marks onsaid sample assembly to align said at least one magneto-resistive readsensor with said sample trench.
 17. The method of claim 14, said headmodule further comprising at least one write head configured tomagnetize the nanoparticles.
 18. The method of claim 14, said headmodule further comprising: a plurality of pairs of write heads andmagneto-resistive read sensors spaced apart from each adjacent pair ofsaid write heads and said magneto-resistive read sensors by a firstdistance, and said sample assembly further comprising: a plurality ofparallel sample trenches spaced apart from each adjacent sample trenchby said first distance, the method further comprising, sampling aplurality of magnetic servo alignment marks formed in proximity to oneor more of the parallel sample trenches using at least one of themagneto-resistive servo read sensors; magnetizing said nanoparticleswith at least one of the write heads; and detecting said nanoparticleswith said magneto-resistive read sensors.
 19. The method of claim 18,wherein the sampling and the magnetizing are performed simultaneously ina single sweep of the head module.
 20. The method of claim 14, furthercomprising either: displaying a positive-detection indication for thepredetermined antigen in response to detecting the predeterminedantigen; or displaying a negative-detection indication for thepredetermined antigen in response to not detecting the predeterminedantigen.
 21. The method of claim 14, further comprising applying a DCvoltage to the substrate, wherein the substrate is a Peltier substrate,and wherein applying the DC voltage to the substrate freezes one or morebiological samples in the sample trench.
 22. The method of claim 14,further comprising: exposing at least partially unbound target antigensto said second set of antibodies bonded to said nanoparticles, whereinsaid second set of antibodies bond with at least some of said at leastpartially unbound target antigens; bonding a third set of antibodies tosaid nanoparticles; and exposing at least partially unbound targetantigens to said third set of antibodies bonded to said nanoparticles.23. The method of claim 14, further comprising: forming a plurality ofmagnetic servo alignment marks on said sample assembly, the plurality ofmagnetic servo alignment marks being configured to facilitate aligningsaid head module with said sample trench; placing said head module incontact with an upper surface of said outer layer; aligning said headmodule with said sample trench utilizing the plurality of magnetic servoalignment marks; detecting said target antigens in said sample trenchvia the nanoparticles using a magneto-resistive servo read sensor of thehead module; and identifying one or more of the target antigens in theat least one sample trench.
 24. The method of claim 23, furthercomprising at least one of: magnetizing at least some of thenanoparticles using a write head of the head module; and demagnetizingat least some of the nanoparticles using the write head of the headmodule.
 25. A method comprising: forming an outer layer on a base layer;forming a plurality of parallel-oriented sample trenches and alignmenttrenches within the outer layer; forming a base layer in each sampletrench and each alignment trench; forming a plurality of magneticservo-alignment marks in each alignment trench; aligning at least onewrite element and at least one read sensor along an X-axis of the atleast one sample trench using the servo-alignment marks: bonding a firstset of antibodies within said at least one sample trench on a firstsurface of the base layer; bonding at least some of the first set ofbonded antibodies to one or more target antigens; bonding a second setof antibodies to nanoparticles; and bonding at least some of the secondset of antibodies bound to the nanoparticles to one or more targetantigens bound to one of the first set of antibodies.
 26. The method asrecited in claim 25, further comprising at least one of: detectingmagnetized nanoparticles using a read sensor of a head module; anddemagnetizing one or more magnetized nanoparticles, and wherein each ofthe detecting and the demagnetizing comprises sweeping the head moduleover the nanoparticles.